Abstract Background : RAB20, a member of the RAS GTPase oncogene family, promotes tumorigenesis in several cancers with poor survival outcomes but its role in penile squamous cell carcinoma (PSCC) remains unclear. Here, comprehensive genomic profiling was performed on eight PSCC and normal tissue pairs and revealed that RAB20 is upregulated in tumors, especially in metastatic lymph nodes. We aimed to explore the clinical significance and oncogenic effect of RAB20 on PSCC and to identify its specific mechanisms in tumor progression. Methods: RT-qPCR and Western blotting were performed on PSCC tissue pairs and our newly established PSCC cell lines to examine the RAB20 expression pattern. The clinical relevance and prognostic value of RAB20 were validated by immunohistochemistry in samples from 259 PSCC patients, the largest cohort to date. Cell proliferation, migration, colony formation, and cell cycle assays were performed along with analysis of a nude mouse tumorigenesis model to explore RAB20’s oncogenic functions. RAB20-mediated G2/M phase cell cycle arrest mechanisms were further demonstrated by bioinformatics analysis and Western blotting. Results: RAB20 expression was upregulated in PSCC tissues, especially in metastatic lymph nodes. High RAB20 expression in PSCC was associated with T, N, and M status, extranodal extension and clinical stage (P < 0.01). Survival analysis indicated that RAB20 was an unfavorable independent prognostic indicator (p = 0.011, HR = 2.090; 95% Cl: 1.183–4.692), and patients with high expression experienced shorter 5-year cancer‐specific survival (P < 0.001). Furthermore, knockdown of RAB20 inhibited cell growth and tumorigenesis in vitro and in vivo. Mechanistic studies indicated that RAB20 depletion arrested the PSCC cell cycle at G2/M via the Chk1/cdc25c/cdc2-cyclinB1 pathway. Conclusions: RAB20 promotes PSCC progression, predicting advanced disease with poor outcomes. RAB20 could be a promising prognostic biomarker and potential therapeutic target for PSCC.
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